Congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease (CHF/ARPKD) is a genetic disease characterized by bilateral renal cystic lesions and progressive liver disease. It occurs in approximately 1 in 20,000 live births. Although severely affected neonates may die in infancy from pulmonary hypoplasia (resulting from large renal cysts), survival rates have significantly increased because of recent advances in neonatal care. Most affected patients will go on to develop progressive kidney and liver diseases with variable rates of deterioration. Portal hypertension is the major cause of morbidity associated with CHF, causing hypersplenism and esophageal varices. Currently, only symptomatic therapy is available, with a small subset of patients requiring liver transplantation as the last resource. The goal of this study is to understand the mechanism of liver fibrosis in CHF/ARPKD. TGF-beta is believed to be the major pro-fibrogenic stimulus in almost all forms of liver fibrosis by mediating the differentiation of multiple cell types in the liver, while CCN2/CTGF is a major downstream effecter of TGF-beta in fibrosis. The underlying hypothesis is that TGF-beta signaling in this disorder is abnormal, resulting in altered interactions between biliary epithelial cells and portal fibroblasts, leading to fibrogenesis. The planned experiments will be carried out in a CHF rat model with three-dimensional and organotypic cultures of primary cells in culture. The model will be utilized to characterize TGF-beta and CCN2/CTGF signaling in biliary epithelial cells and portal fibroblasts from the PCK rat liver by expression analysis and functional studies. This model will also be utilized to elucidate the role of TGF-beta and other growth factors in biliary epithelial cell function, as well as their interactions with portal fibroblasts and hepatic stellate cells in CHF- associated fibrosis, utilizing expression assays, immunolfuorescence and functional assays in the co-culture system. The proposed study will provide significant insight into the mechanism of fibrosis in CHF. The understanding of the unique mechanism of fibrous in CHF will hold important implications for identifying potentially effective therapies to prevent or reverse the process of fibrosis and future design of anti-fibrosis treatments for CHF patients. [unreadable] [unreadable] [unreadable] [unreadable]